Abstract: The twin goals of this proposal are to (1) to define the mechanisms underlying the alymphatic nature of the retina by developing novel insights into the biology of the endogenous lymphangiogenesis inhibitor soluble vascular endothelial growth factor receptor-2 (sVEGFR-2);and (2) enable the principal investigator to develop the skills and experiences necessary to become an independent physician-scientist with a focus on studying ocular angiogenesis. Angiogenesis is fundamentally important for a vast array of physiological processes including development and wound healing, and it comprises the intertwined growth and development of the blood (hemangiogenesis) and lymphatic (lymphangiogenesis) vasculatures. The retina is one of the very few tissues in the body that is served by blood vessels yet remains alymphatic. The mechanisms subserving this divergence in the vascular infrastructure of the retina are unknown. Recently our group reported the existence of a novel splice variant of VEGFR-2 that is the first described endogenous molecule that inhibits lymphangiogenesis but not hemangiogenesis (Albuquerque et al. Nat Med 2009). In new and exciting studies, we found that sVEGFR-2, which is essential for the development of an alymphatic cornea, is expressed in the human and mouse retina, and that knockdown of sVEGFR-2 induced the development of lymphatic vessels in the retina. We will test the hypothesis that sVEGFR-2 is responsible for the alymphatic nature of the retina via the following 3 aims: (1) We will define the spatial and temporal expression and function of sVEGFR-2 in the mouse retina during development and in the adult;(2) We will define the molecular basis and cellular origin of lymphatics in the mouse retina after inhibition of sVEGFR-2 function;(3) We will define the mechanisms by which sVEGFR-2 and VEGF-C influence the function of cells that assume a lymphatic endothelial phenotype in the retina. This study will activate new concepts in sVEGFR-2 biology, and yield novel insights into the mechanisms underlying the alymphatic nature of the retina and develop the career of the principal investigator as a clinician scientist. PUBLIC HEALTH RELEVANCE: Narrative: The retina is one of the very few tissues in the body that is served by blood vessels yet remains alymphatic. The mechanisms subserving this divergence in the vascular infrastructure of the retina are unknown. We discovered a naturally occurring molecule (sVEGFR-2) that selectively blocks lymphatic but not blood vessels. By molecularly uncoupling these intertwined processes, we introduce a new research tool that can be used to specifically study lymphatic vascular biology in the retina.